Process for the alkylation of pyridine derivatives

ABSTRACT

2-R,4-Y-PYRIDINE     A PROCESS FOR ALKYLATING PYRIDINIC DERIVATIVES IS DISCLOSED, AND MORE PARTICULARLY THE ALKYLATION OF DERIVATIVES OF ISONICOTINIC ACID, IN ORDER TO OBTAIN 2-ALKYL DERIVATIVES HAVING THE FORMULA: WHEREIN R REPRESENTS AN ALKYL GROUP HAVING FROM 1 TO 4 CARBON ATOMS AND Y REPRESENTS A HYDROGEN ATOM OR A FUNCTIONAL GROUP COOR&#39;&#39; (WHEREIN R&#39;&#39; IS AN ALKYL GROUP HAVING FROM 1 TO 4 CARBON ATOMS), CONH2 OR CN, THE PROCESS BEING CHARACTERIZED IN THAT THE PYRIDINIC DERIVATIVE IS TREATED IN AN ACID AQUEOUS SOLUTION WITH A MIXTURE PREPARED SEPARATELY FROM A DIALKYLKETONE HAVING FROM 4 TO 6 CARBON ATOMS AND FROM HYDROGEN PEROXIDE, IN THE PRESENCE OF A FERROUS SALT, UNDER ATMOSPHERIC PRESSURE AND AT A TEMPERATURE BETWEEN 0* AND 50*C.

United States Patent ()fiice Patented Mar. 6, 1973 US. Cl. 260-295 R 9Claims ABSTRACT OF THE DISCLOSURE A process for alkylating pyridinicderivatives is disclosed, and more particularly the alkylation ofderivatives of isonicotinic acid, in order to obtain 2-alkyl derivativeshaving the formula:

wherein R represents an alkyl group having from 1 to 4 carbon atoms andY represents a hydrogen atom or a functional group COOR' (wherein R isan alkyl group having from 1 to 4 carbon atoms), CONH or ON, the processbeing characterized in that the pyridinic derivative is treated in anacid aqueous solution with a mixture prepared separately from adialkylketone having from 4 to 6 carbon atoms and from hydrogenperoxide, in the presence of a ferrous salt, under atmospheric pressureand at a temperature between and 5 0 C.

The present invention relates to a process for the alkylation ofpyridine derivatives, and more particularly the alkylation ofderivatives of isonicotinic acid, for obtaining in particular 2-alkylderivatives thereof.

The alkyl derivatives obtained according to the present invention may beprofitably used in the pharmaceutical field. More particularly, the2-ethyland the 2-propyl-derivatives are useful intermediates for thepreparation of 2- ethyland 2-propyl-isonicotin-thioamides which arecommercial products of considerable interest for their hightuberculostatic activity.

The alkyl derivatives of isonicotinic esters are transformed accordingto known methods into amides and these latter into nitriles from whichthe alkyl-isonicotinthioamides are obtained.

It is well known to prepare esters of 2-alkyl-isonicotinic acid startingfrom an ethyl-acyl-pyruvate which is then transformed successively into2-alkyl-5-cyano-4-carbethoxy-6-pyridone, 2-alkyl-4-carboxy-6-pyridone,and 2- alkyl-S-chloroisonicotinate.

Such a process has, however, the drawback of being rathercomplicated'and in requiring numerous reaction steps thereby becomingrather expensive.

It is an object of the present invention, therefore, to provide aprocess for the alkylation of pyridinic derivatives, and moreparticularly for the alkylation of isonicotinic acid derivatives, forpreparing 2-alkyl-derivatives thereof that shall be simple, practicaland cheap and that shall be free of the drawbacks of the knownprocesses.

According to this invention, a process is provided for alkylating thepyridinic derivatives, and more particularly the alkylation ofderivatives of isonicotinic acid, for obtaining in particular 2-alkylderivatives of the formula:

wherein R represents an alkyl group having from 1 to 4 carbon atoms andY represents a hydrogen atom or a functional group COOR (in which R isan alkyl group having from 1 to 4 carbon atoms), CONH or CN; the processbeing characterized in that the pyridinic derivative is treated in anacid aqueous solution with a mixture prepared separately from adialkylketone having from 4 to 6 carbon atoms and from hydrogenperoxide, in

the presence of a ferrous salt, under atmospheric pressure and attemperatures between 0 and 50 C.

According to a preferred embodiment of the invention, the alkylationreaction is carried out at a temperature of from 0 to 50 C. underatmospheric pressure by adding to an acid aqueous solution of thepyridinic derivative contemporaneously and with constant stirring, amixture prepared separately of a dialkylketone and hydrogen peroxide andan aqueous saturated solution of a ferrous salt.

The reaction is very fast. The addition of the reactants is carried outgradually over a period of 15-30 minutes in order that the temperatureshall not rise too much.

When the addition of the reactants is ended, the mixture is poured overice, neutralized with sodium bicarbonate, and the desired product isextracted with a solvent that is immiscible with water.

By fractional distillation the solvent and the products are thenrecovered. The unconverted product is recovered by fractionaldistillation and then recycled.

When the two alkyl groups of the dialkylketone are different, it ispossible to form derivatives of the pyridinic compound which contain inthe 2 position either the one or the other of the two different alkylgroups of the ketone. Thus, for instance, by using methylethylketone,besides the Z-ethyl-derivative of the pyridinic compound there also formtraces of methyl-derivative; by using diethylketone instead ofmethyl-ethyl-ketone the same products are obtained but without traces ofthe methylderivative.

The reaction (in the case of e.g. methyl-alkyl-ketone) may berepresented in the following way:

CH COOH 11 0 N R wherein Y represents a hydrogen atom or a functionalgroup chosen from ester, amide and nitrile groups and wherein Rrepresents an alkyl group having from 1 to 4 carbon atoms.

Instead of the dialkylketone-hydrogen peroxide mixture it is possible touse in the process according to this invention the peroxidated productprepared separately from the ketone and the hydrogen peroxide.

The pyridinic derivative is present in solution as the salt of a strongacid, preferably as the salt of sulphuric acid.

Of the pyridinic derivatives, the esters of isonicotinic acid give thebest results inasmuch as they allow a much easier separation of thereaction products from the aqueous phase and because, moreover, theyallow an easier separation of the components present in the aqueousphase by fractional distillation.

As the ferrous salt, ferrous sulphate is preferably used. This salt isused in quantities equimolar with respect to the peroxidic compoundformed from the reaction of the dialkylketone with hydrogen peroxide.

For each mole of dialkylketone 0.2-1 mole of H is used. For each mole ofpyridinic derivative there are used from 0.5 to 5 moles, and preferablyfrom 1-2 moles, of the ketone peroxide.

For each mole of pyridinic derivative there are used from 1 to 2 molesof sulphuric acid, so as to obtain an aqueous solution having a clearlyacid pH (p-H 2).

Moreover, the process according to the present invention also enablesone to obtain if desired the 2,6-dialkyl derivatives. The production ofthese compounds depends on the molar ratio between the ketone peroxideand the pyridinic derivative as well as on the conversion degree of thealkylation reaction. In fact both the conversion and the ratio of thedialkyl derivative to the monoalkyl derivative increase as the molarratio is increased.

The present invention will now be still further illustrated by thefollowing detailed working examples.

EXAMPLE 1 The hydroperoxide of the dialkyl-ketone was preparedseparately in the following way:

20 ml. of hydrogen peroxide at 34% b.w. (=130 vol.) and ml. of methanolwere added to 32 ml. of methylethyl-ketone (MEK). Thereupon, withcooling in a bath at 0 C. and While stirring, there were added 5 ml. ofconcentrated sulphuric acid at 98%. The mixture was then left to restfor 30 minutes, the organic layer that separated was then decanted andwashed several times with water (in order to eliminate the unreacted H 0and thereupon the titer in peroxide was iodometrically determined. Theorganic layer still contained unconverted MEK which was then recoveredat the end of the reaction b distillation.

The peroxidated product thus obtained was poured dropwise while stirringinto a solution containing 30 g. of ethyl ester of isonicotinic acid, 20ml. of concentrated sulphuric acid, and 80 ml. of Water.Contemporaneously an aqueous saturated solution of ferrous sulphate wasdripped in a quantity equimolar with respect to the peroxidatedderivative. The temperature rose during the reaction from 0 to 30 C.

When the addition was ended (in about -30 minutes) the mixture waspoured onto ice, then neutralized with sodium bicarbonate and extractedwith ether. 30-32 g. of product were thus obtained, which were thenanalyzed by gas-chromatography.

The ratio between the peroxidated product and the ester of isonicotinicacid determines the degree of conversion and the composition of thereaction product, as indicated by the following table:

Molar ratios otinic Products ethyl- Peroxide ester Conversion 2-ethyl2,6-diethyl C./15 mm. Hg, and the desired 2-ethyl derivative up to C./l5mm. Hg Were collected as separate overhead fractions, leaving the2,6-diethyl derivative as the distillation residue.

Using diethyl-ketone instead of the methyl-ethyl-ketone similar resultswere obtained, but the yields with respect to the peroxide were in thiscase about half.

EXAMPLE 2 According to the procedures described in Example 1 above, 0.07mole of peroxidated methyl-ethyl-ketone and 0.07 mole of ferroussulphate were added to a solution of 4.6 g. of the nitrile ofisonicotinic acid in 30 ml. of water and 5 ml. of concentrated sulphuricacid.

The raw reaction product was chromatographed on a silica gel of 0.05-0.2mm. (Merck-Darmstadt), eluting with a mixture of hexane and ethylacetate (9:1 in volume). 2 g. of 2-ethylisonicotin-nitrile wereseparated therefrom, which was identified via transformation into2-ethyl-isonicotin-thioamide (M.P. 166 C.) by treatment with hydrogensulphide.

The remaining part of the raw reaction product consisted of the startingproduct the 2,6-diethyl derivative, and traces of the Z-methylderivatvie.

EXAMPLE 3 According to the procedures described in Example 1 above, 0.05mole of peroxidated methyl-ethyl-ketone and 0.05 mole of ferroussulphate Were added to a solution of 6 g. of isonicotin-amide in 30 ml.of Water and 5 ml. of concentrated sulphuric acid.

After neutralization with sodium bicarbonate, the reaction mixture wasextracted with chloroform. The solvent was then evaporated and theresidue was chromatographed on a silica gel of 0.05-0.2 mm. (MerckDarmstadt), thereupon eluting with a mixture of ethyl acetate andmethanol (9:1 by volume). 1.7 g. of 2-ethyl-isonicotin-amide, having ameling point of 133 C., were separated in this manner.

EXAMPLE 4 In this case the same procedures were followed as in Example 1above, but using methyl-n-propyl-ketone instead of methyl-ethyl-ketone.In this way there were obtained results entirely analogous to thosedescribed in Example 1, the only difference being that the reactionproduct was constituted by the 2-propyland the 2,6-dipropyl-derivativesof the ethyl ester of isonicotinic acid instead of by the correspondingethyl-derivatives. The ethyl ester of 2-propyl-isonicotinic acid wascharacterized by transformation into the amide (M.P. 135 C.)

EXAMPLE 5 20 ml. of H 0 at 34% were mixed together with 14.1 g. ofmethyl-ethyl-ketone and 20 ml. of methanol, then, while cooling (at 0C.) and stirring, there were added 5 ml. of concentrated H 80 Themixture thus obtained was left to rest for 30 minutes and was thendripped, while stirring, into a solution of 15 g. of the ethyl ester ofisonicotinic acid and 5 ml. of concentrated H 50 in 50 ml. of water.

At the same time, there was dripped a solution of 30 g. of FeSO .7H O in50 ml. of water. During the reaction the temperature rose from 0 to 30C.

When the reaction was ended, the mixture was poured over ice,neutralized with sodium bicarbonate, and extracted with ethyl ether.After evaporation of the solvent, the residue was analyzed bygas-chromatography.

The conversion turned out to be 45% while the product obtained consistedby 90% of the Z-ethyland 10% of the 2,6-diethyl-derivative of the ethylester of isonicotinic acid.

A similar reaction conducted on pyridine with methylethyl-ketone gavemixtures of isomers wherein 2-ethylpyridine and 4-ethyl-pyridineprevailed.

in order to obtain 2-alkyl derivatives of the formula:

wherein R represents an alkyl group having from 1 to 4 carbon atoms andY represents a hydrogen atom or a functional group COOR (wherein R is analkyl group having from 1 to 4 carbon atoms), CONH or CN, wherein thepyridyl derivative is treated in an acid aqueous solution with a mixtureprepared separately from a dialkylketone having from 4 to 6 carbon atomsand from hydrogen peroxide, in the presence of ferrous sulphate, underatmospheric pressure and at a temperature between and 50 C.

2. A process according to claim 1, wherein the pyridyl derivative is anisonicotinic acid derivative.

3-. A process according to claim 2, wherein the aqueous solution hasbeen rendered acid by sulphuric acid.

4. A process according to claim 3, wherein for each mole of pyridylderivative there are used from 1 to 2 moles of sulphuric acid.

5. A process according to claim 1, wherein instead of the mixture ofketone and hydrogen peroxide there is used the peroxidated productprepared separately from the ketone and hydrogen peroxide.

6. A process according to claim 5, wherein for each mole of ketone thereare used from 0.2 to 1 mole of H 0 7. A process according to claim 5,wherein for each mole of pyridyl derivative there are used from 0.5 to 5moles of the ketone.

8. A process according to claim 5, wherein for each mole of pyridylderivative there are used from 1 to 2 moles of the ketone.

9. A process according to claim 1, wherein the ferrous sulphate is usedin an equimolar quantity with respect to the peroxide.

References Cited UNITED STATES PATENTS 3,591,592 7/1971 Anderson 260-29OR OTHER REFERENCES Libermann et a1., Bull. Soc. Chim., France, pages687- 694 (1958).

ALAN L. ROTMAN, Primary Examiner U.S. Cl. X.R.

260-290 R, 294.9, 295 AM, 294.8 E

